Bevacizumab-Induced Normalization of Blood Vessels in Tumors Hampers Antibody Uptake

Abstract

In solid tumors, angiogenesis occurs in the setting of a defective vasculature and impaired lymphatic drainage that is associated with increased vascular permeability and enhanced tumor permeability. These universal aspects of the tumor microenvironment can have a marked influence on intratumoral drug delivery that may often be underappreciated. In this study, we investigated the effect of blood vessel normalization in tumors by the antiangiogenic drug bevacizumab on antibody uptake by tumors. In mouse xenograft models of human ovarian and esophageal cancer (SKOV-3 and OE19), we evaluated antibody uptake in tumors by positron emission tomographic imaging 24 and 144 hours after injection of Zr-IgG (SKOV-3) before or after treatment with bevacizumab. Intratumor distribution was assessed by fluorescence microscopy along with mean vessel density (MVD) and vessel normalization. Notably, bevacizumab treatment decreased tumor uptake and intratumoral accumulation compared with baseline in the tumor models relative to controls. Bevacizumab treatment also reduced MVD in tumors and increased vessel pericyte coverage. These findings are clinically important, suggesting caution in designing combinatorial trials with therapeutic antibodies due to a possible reduction in tumoral accumulation that may be caused by bevacizumab cotreatment. Cancer Res; 73(11); 3347-55. Ó2013 AACR.

Molecular Drug Imaging: 89Zr-Bevacizumab PET in Children with Diffuse Intrinsic Pontine Glioma

“…A difficulty in performing such a study with DIPG patients is that current DIPG trials involve multiagent therapy regimens. The finding that bevacizumab can reduce the penetration of other drugs into tumors (22,23) underlines the need for labeled-drug imaging in this multiagent setting. On the other hand, in contrast to single-agent settings, multiagent therapy may confound the association of the imaging biomarker and outcome-so that clinical validation of this immuno-PET method as a predictive biomarker of the response to therapy requires larger datasets.…”

Translational Impact of Nanoparticle–Drug Conjugate CRLX101 with or without Bevacizumab in Advanced Ovarian Cancer

“…The vessel "normalization" hypothesis suggests that superior antitumor efficacy is observed when combining bevacizumab with chemotherapy because the antiangiogenic agent structurally and functionally normalizes some of the remaining abnormal tumor vasculature, leading to improved intratumoral drug delivery and distribution, thus enhancing chemotherapy efficacy (39). However, some recent studies have shown the opposite, that chemotherapy drug delivery is impaired as a result of bevacizumab therapy causing vascular damage and tumor necrosis (40,41). Because the delivery of CRLX101 to tumor cells relies in part on the leaky nature of tumor vasculature, we evaluated whether combining CRLX101 with bevacizumab would result in improved, impaired, or unaffected CRLX101 drug delivery to tumors.…”

89Zr-Bevacizumab PET Visualizes Heterogeneous Tracer Accumulation in Tumor Lesions of Renal Cell Carcinoma Patients and Differential Effects of Antiangiogenic Treatment

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